- YESCARTA is a chimeric antigen receptor T (CAR T) cell therapy that is custom-made for each patient from his or her own T
cells.
- Once reinfused into the patient, the CAR T cells are able to find and attack cancer cells that normal T cells cannot
detect.
MISSISSAUGA, ON, Feb. 19, 2019 /CNW/ - Gilead Sciences
Canada, Inc. announced today that Health Canada has granted a Notice of Compliance (NOC) for Yescarta™ (axicabtagene ciloleucel),
a new chimeric antigen receptor T (CAR T) cell therapy for the treatment of adult patients with relapsed or refractory large
B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise
specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma
(transformed follicular lymphoma, or TFL).1 YESCARTA is not indicated for the treatment of patients with primary
central nervous system lymphoma.
YESCARTA is a CAR T cell therapy, also known as a form of immunotherapy, that is custom-made for each patient from his or her
own T cells – a type of white blood cell that is part of the immune system and that recognizes and kills foreign cells. The
process works by removing the patient's T cells and genetically altering them with chimeric antigen receptors (CARs). Once
reinfused into the patient, the CAR T cells are able to find and attack cancer cells that normal T cells cannot detect.
This cell therapy induces complete response (no detectable cancer) in a proportion of patients with relapsed or refractory
DLBCL and primary mediastinal large B-cell lymphoma, which are aggressive forms of non-Hodgkin lymphoma (NHL).
"CAR T therapy is at the forefront of personalized medicine and in the treatment of lymphoid cancers," said Dr. John Kuruvilla, MD, FRCPC, ZUMA-1 Investigator and Hematologist in the Division of Medical Oncology and
Hematology at Princess Margaret Hospital. "I have seen first-hand how YESCARTA has transformed the prognosis and outlook for a
patient who would otherwise have limited treatment options. This treatment offers a reliable process that is completely
customized for each individual patient."
NHL is the fifth most common cancer diagnosed in Canada.2 In 2017, an estimated
8,300 Canadians were diagnosed with NHL and 2,700 Canadians died from the disease.3 DLBCL is the most common
aggressive type of NHL and accounts for about 30-40 per cent of all cases.4 Historically, when treated with the
current standard of care, patients with relapsed or refractory large B-cell lymphoma had a median overall survival of
approximately six months, with only seven per cent attaining a complete response.5 Currently, patients with large
B-cell lymphoma in second or later lines of therapy have poor outcomes and high unmet need, since nearly half of them either do
not respond or relapse shortly after transplant.
"There is an unmet need for new therapies for patients with relapsed or refractory large B-cell lymphoma and who face an
unfavourable prognosis," said Elizabeth Lye, Director of Research & Programs at Lymphoma
Canada. "This approval is an important milestone as it provides new hope for Canadians living with this disease."
YESCARTA will be manufactured by Kite, a Gilead Company (Kite) at its commercial manufacturing facility in El Segundo, California. In the ZUMA-1 pivotal trial, Kite demonstrated a 99 per cent manufacturing success
rate with a median manufacturing turnaround time of 171 days.6 This is important for patients given the
potential for rapid disease progression in this population.
"This regulatory approval brings YESCARTA one step closer to adult Canadian patients with relapsed or refractory large B-cell
lymphoma who currently have few or no treatment options available to them," said John McHutchison,
AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead Sciences. "YESCARTA brings a new and exciting option
to patients and the physicians who treat them."
YESCARTA Pivotal Trial Results
The approval of YESCARTA was based on the ZUMA-1 pivotal trial. In the single-arm trial, 72 per cent of patients (n=73/101)
who received YESCARTA responded to therapy, with 51 per cent (n=52/101) achieving a complete response (as assessed by an
independent review committee, median follow-up of 15.4 months).
In the study, 12 per cent of patients experienced Grade 3 or higher cytokine release syndrome (CRS) and 31 per cent
experienced Grade 3 or higher neurologic adverse reactions. The most common Grade 3 or higher adverse reactions include
encephalopathy (30%), unspecified pathogen infection (19%), CRS (12%), bacterial infection (8%),
aphasia (7%), viral infection (6%), delirium (6%), hypotension (6%) and hypertension (6%). Grade 5 (fatal)
adverse events were reported in 4 patients (anoxic brain injury [secondary to cardiac arrest which occurred in the setting of
CRS], histiocytosis haematophagic (HLH), intracranial hemorrhage in the setting of thrombocytopenia and pulmonary embolism).
Serious adverse reactions occurred in 55 per cent of patients. The most common serious adverse reactions (? 2%) include
encephalopathy (18%), lung infection (7%), pyrexia (7%), pneumonia (6%), confusional state (5%), febrile neutropenia (5%),
aphasia (4%), atrial fibrillation (4%), cardiac arrest (4%), urinary tract infection (4%), acute kidney injury (3%), agitation
(3%), ejection fraction decreased (3%), hypotension (3%), hypoxia (3%), neutropenia (3%), somnolence (3%), atrial flutter (2%)
and delirium (2%). Seventeen (16%) patients required intensive care unit admission.
The most common non-hematological adverse reactions ( in ? 20%) include CRS (93%), encephalopathy (58%), fatigue (43%),
decreased appetite (41%), fever (40%), headache (40%), diarrhea (35%), nausea (31%), tremor (31%), tachycardia (29%), cough
(29%), unspecified pathogen infection (28%), hypotension (27%), vomiting (23%), dizziness (21%), constipation (20%), and edema
(20%).
IMPORTANT SAFETY INFORMATION
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1 In Canada, turnaround time is expected to be slightly
longer (about 22 days), due to shipping, border crossing, and other logistical issues.
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The YESCARTA Product Monograph has a SERIOUS WARNINGS AND PRECAUTIONS BOX regarding the risks of CYTOKINE RELEASE SYNDROME
and NEUROLOGIC ADVERSE REACTIONS
- Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving
YESCARTA. Delay YESCARTA treatment if a patient has active uncontrolled infection or inflammatory disorders, active
graft-versus-host disease (GVHD) or unresolved serious adverse reactions from prior therapies. Monitor for CRS after treatment
with YESCARTA. Provide supportive care, tocilizumab, or tocilizumab and corticosteroids, as needed.
- Neurologic adverse reactions, including fatal or life-threatening reactions, occurred in patients receiving
YESCARTA, including concurrently with CRS or independently of CRS. Monitor for neurologic adverse reactions after treatment
with YESCARTA. Provide supportive care, tocilizumab (if with concurrent CRS), or corticosteroids, as needed.
- YESCARTA should be administered by experienced health professionals at specialized treatment centres
Cytokine Release Syndrome (CRS)
CRS, including fatal or life-threatening reactions, occurred following treatment with YESCARTA. In ZUMA-1, CRS occurred in 93%
of patients receiving YESCARTA, including ? Grade 3 (Lee grading system) CRS in 12% of patients. The median time to onset was 2
days (range: 1 to 12 days) and the median duration of CRS was 7 days (range: 2 to 29 days, with the exception of one observation
of 58 days). The most common manifestations of CRS (>10%) include fever (76%), hypotension (41%), tachycardia (21%), hypoxia
(21%), and chills (19%). CRS can cause end organ dysfunctions. Serious events that may be associated with CRS include cardiac
arrhythmias (including atrial fibrillation/flutter and ventricular tachycardia), hypoxia, hypotension, ejection fraction
decreased, cardiac arrest, cardiac failure, renal insufficiency/failure, metabolic acidosis, aspartate aminotransferase
increased, alanine aminotransferase increased, blood bilirubin increased, coagulopathy, capillary leak syndrome, and
hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
Ensure that 4 doses of tocilizumab are available prior to infusion of YESCARTA. Monitor patients at least daily for 7 days at
the specialized healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of
CRS for 4 weeks after infusion. Counsel patients to remain within proximity of a specialized clinical facility for at least 4
weeks and seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute
treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.
Neurologic
Severe neurologic adverse reactions have been very commonly observed in patients treated with YESCARTA, which could be
life-threatening or fatal. Neurologic adverse reactions occurred in 65% of patients, 31% of whom experienced Grade 3 or higher
(severe or life threatening) adverse reactions. The median time to onset was 5 days (range 1 to 17 days). The median
duration was 13 days, with a range of 1 to 191 days. Ninety-eight per cent (98%) of all patients recovered from neurologic
adverse reactions.
The most common signs or symptoms (>10%) associated with neurologic adverse reactions include encephalopathy (37%), tremor
(31%), confusional state (27%), aphasia (18%), and somnolence (17%). Serious adverse reactions including encephalopathy,
aphasia, delirium, and seizures have been reported in patients administered YESCARTA. Fatal and serious cases of cerebral edema
have been reported in patients treated with YESCARTA.
Patients with a history of CNS disorders such as seizures or cerebrovascular ischemia may be at increased risk.
Hypersensitivity Reactions
Allergic reactions may occur with the infusion of YESCARTA. Serious hypersensitivity reactions including anaphylaxis, may be
due to dimethyl sulfoxide (DMSO) or residual gentamicin in YESCARTA.
Serious Infections
Severe or life-threatening infections occurred in patients after YESCARTA infusion. In ZUMA-1, infections (all grades)
occurred in 38% of patients. Grade 3 or higher infections occurred in 25% of patients, including infections with an unspecified
pathogen, bacterial infections, and viral infections. YESCARTA should not be administered to patients with clinically
significant active infections. Monitor patients for signs and symptoms of infection before and after YESCARTA infusion and
treat appropriately. Administer prophylactic anti-microbials according to local guidelines.
Febrile neutropenia was observed in 35% of patients after YESCARTA infusion and may be concurrent with CRS. In the event
of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids and other supportive care as
medically indicated.
Viral Reactivation
Reactivation of hepatitis B virus (HBV) and human herpesvirus 6 (HHV-6) can occur in patients treated with drugs directed
against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for
manufacturing.
Prolonged cytopenias
Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and YESCARTA infusion. In
ZUMA-1, Grade 3 or higher prolonged cytopenias (cytopenias not resolved by Day 30 following YESCARTA infusion) included
thrombocytopenia (27%), neutropenia (31%), lymphopenia (99%), and anemia (17%). Monitor blood counts after
YESCARTA infusion.
Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with YESCARTA. In ZUMA-1,
hypogammaglobulinemia occurred in 17% of patients. B-cell aplasia was observed in 60% and 77% of patients at baseline and at 3
months, respectively. Monitor immunoglobulin levels after treatment with YESCARTA and manage using infection precautions,
antibiotic prophylaxis and immunoglobulin replacement in case of recurrent infections.
Due to prolonged hypogammaglobulinemia and B-cell aplasia, it is not known if patients will respond to vaccination following
treatment with YESCARTA. The safety of immunization with live viral vaccines during or following YESCARTA treatment has not
been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting
chemotherapy, during YESCARTA treatment, and until immune recovery following treatment with YESCARTA.
Secondary Malignancies
Patients treated with YESCARTA may develop secondary malignancies. They should be monitored life-long for secondary
malignancies. In the event that a secondary malignancy occurs, contact the company to obtain instructions on patient samples to
collect for testing.
Driving and Operating Machinery
Due to the potential for neurologic events, including altered mental status or seizures, patients receiving YESCARTA are
at risk for altered or decreased consciousness or coordination in the 8 weeks following YESCARTA infusion. Advise patients
to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous
machinery, during this initial period.
Endocrine and Metabolism
Tumour lysis syndrome (TLS)
TLS may occur in patients treated with YESCARTA. To minimize the risk of TLS, patients with elevated uric acid or high tumour
burden should receive prophylactic treatment (allopurinol, or an alternative prophylaxis) prior to YESCARTA
infusion.
Adverse Reactions
For adverse reactions please refer to YESCARTA Pivotal Trial Results earlier in this release.
About Kite
Kite, a Gilead Company, is a biopharmaceutical company based in Santa Monica, California.
Kite is engaged in the development of innovative cancer immunotherapies. The company is focused on chimeric antigen receptor and
T cell receptor engineered cell therapies. For more information on Kite, please visit www.kitepharma.com.
About Gilead Sciences
Gilead Sciences, Inc. is a research-based biopharmaceutical company that discovers, develops and commercializes innovative
medicines in areas of unmet medical need. The company strives to transform and simplify care for people with life-threatening
illnesses around the world. Gilead has operations in more than 35 countries worldwide, with headquarters in Foster City, California. Gilead Sciences Canada, Inc. is the Canadian affiliate of Gilead Sciences, Inc.,
and was established in Mississauga, Ontario in 2006. For more information on Gilead Sciences,
please visit the company's website at www.gilead.com.
Forward-Looking Statement
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of
1995 that are subject to risks, uncertainties and other factors, including the risk that physicians may not see the benefits of
prescribing YESCARTA for the approved indications; the ability of Kite to continue to manufacture YESCARTA at the
success rates experienced during clinical trials; the availability of certified centers in Canada to provide YESCARTA to patients; and the possibility of unfavorable results from additional clinical
trials involving YESCARTA. All statements other than statements of historical fact are statements that could be deemed
forward-looking statements. These risks, uncertainties and other factors could cause actual results to differ materially from
those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements.
These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended October 31, 2018, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are
based on information currently available to Gilead and Kite, and Gilead and Kite assume no obligation to update any such
forward-looking statements.
Canadian Product Monograph for YESCARTA, including Serious Warnings and Precautions Box, is available at
www.gilead.ca.
YESCARTA, Kite, the Kite logo, Gilead, and the Gilead logo are trademarks of Gilead Sciences, Inc., or its
related companies.
For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public
Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
REFERENCES
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1 YESCARTATM product monograph, February 13,
2019.
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2 Lymphoma Canada "Non-Hodgkin Lymphoma." Available at:
https://www.lymphoma.ca/lymphoma/non-hodgkin-lymphoma. Accessed: January 21, 2019.
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3 Canadian Cancer Society. "Non-Hodgkin lymphoma
statistics." Available at: http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/statistics/?region=on.
Accessed: January 21, 2019.
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4 Raut, L.S. and Chakrabarti, P.P. South Asian Journal of
Cancer. "Management of relapsed-refractory diffuse large B cell lymphoma." Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961873/. Accessed: January 21, 2019.
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5 Crump, M, Neelapu, SS, Farooq, U, et al. Blood. "Outcomes
in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study." Available at: http://www.bloodjournal.org/content/130/16/1800. Accessed: February 11, 2019.
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6 Neelapu, SS, Locke, FL, Bartlett, NL, et al. New England
Journal of Medicine. "Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma." Available at:
http://www.bloodjournal.org/content/130/16/1800 https://www.nejm.org/doi/full/10.1056/NEJMoa1707447/. Accessed: February 8, 2019.
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SOURCE Gilead Sciences, Inc.
View original content: http://www.newswire.ca/en/releases/archive/February2019/19/c3199.html